Bone morphogenetic protein (Bmp) signaling has a central role in craniofacial and tooth development. Moreover, Bmp-signaling is known to be involved in human diseases such as juvenile polyposis syndromes in which mutations in the type I Bmp receptor, BmpR1A, have been discovered. Moreover other studies, that identified mutations in the type II Bmp receptor, BmpRII in families with pulmonary artery hypertension (PAH), uncovered a role for Bmp-signaling in the development or homeostasis of the pulmonary vasculature. A firm understanding about the role of Bmp signaling in craniofacial morphogenesis has been limited by the early embryonic lethality of the Bmp4 and Bmp2 null mutant mice. This research program will directly investigate the function of Bmp4 and Bmp2 in craniofacial organogenesis using conditional gene inactivation studies. We propose to dissect the temporal and tissue specific requirements for Bmp4 and Bmp2 signaling in branchial arch and incisor tooth morphogenesis by using cre recombinase transgenic methods to precisely inactivate or overexpress Bmp ligands. Epithelial-mesenchymal signaling is a central theme in vertebrate organogenesis. In this research program, we propose to study Bone Morphogenetic Protein (Bmp)-signaling in epithelial-mesenchymal interactions during mandibular and tooth development. In the forming mandible, signaling between a specified branchial arch ectoderm and a plastic mesenchyme is thought to regulate mandibular morphogenesis. Recent work also indicates that signaling from pharyngeal endoderm is important for early mandibular morphogenesis. We propose to investigate the role of Bmp-signaling from pharyngeal endoderm in mandibular development. Tooth organogenesis initiates at stereotypical sites within the mandible and maxilla. Moreover, the rodent incisor tooth contains a stem cell niche in the incisor, called the cervical loop, that is necessary for lifelong incisor growth. We propose to study the function of Bmp4 and Bmp2 in development of the incisor cervical loop niche. The incisor is also a valuable system to investigate ameloblast cytodifferentiation along a simple, anterior-posterior axis. Our preliminary data suggest that Bmp4 has a critical role in ameloblast development that we propose to investigate in this research program. PUBLIC HEALTH RELEVANCE: Bmp-signaling has been implicated in human inherited disorders including juvenile polyposis that involve regulation of colonic epithelial growth. Other human genetic studies, that identified mutations in the type II Bmp receptor, BmpRII in families with pulmonary artery hypertension (PAH) uncovered a role for Bmp-signaling in the development or homeostasis of the pulmonary vasculature. This research program will perform in depth investigation of Bmp-signaling during vertebrate development and will therefore provide insight into Bmp function with the long-term goal of uncovering therapeutic avenues for human patients. [unreadable] [unreadable] [unreadable]